1. Field of the Invention
The present invention relates to a series of substituted bis aryl and heteroaryl compounds as described herein. More specifically, the present invention relates to a series of dialkylamino, piperidinyl or piperazinyl substituted his aryl and heteroaryl derivatives. This invention also relates to methods of making these compounds. The compounds of this invention are selective serotonin, 5HT2A, antagonists and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases including diseases associated with the central nervous system. More specifically, the compounds of this invention are useful in the treatment of a variety of sleep disorders.
2. Description of the Art
Chronic insomnia among adults in the United States has been estimated to be present in ten percent of the adult population, and the annual cost for its treatment is estimated at $10.9 billion. JAMA 1997; 278: 2170-2177 at 2170. Chronic insomniacs report elevated levels of stress, anxiety, depression and medical illnesses. The most common class of medications for treating insomnia are the benzodiazepines, but the adverse effect profile of benzodiazepines include daytime sedation, diminished motor coordination, and cognitive impairments. Furthermore, the National Institutes of Health Consensus conference on Sleeping Pills and Insomnia in 1984 have developed guidelines discouraging the use of such sedative-hypnotics beyond 4-6 weeks because of concerns raised over drug misuse, dependency, withdrawal and rebound insomnia. JAMA 1997; 278: 2170-2177 at 2170. Therefore, it is desirable to have a pharmacological agent for the treatment of insomnia which is more effective and/or has fewer side effects than those currently used.
The prevalence of obstructive sleep apnea is estimated to be approximately 1-10% in the adult population, but may be higher in elderly individuals; Diagnostic and Statistical Manual of Mental Disorders 4th ed., American Psychiatric Association, Washington D.C. (1994). Preliminary evidence suggests that having obstructive sleep apnea may contribute to increased susceptibility to cardiovascular complications such as hypertension, cardiac arrhythmias, stroke, and myocardial infarction. Excessive daytime sleepiness is also a major complication.
Currently, the therapies used to treat obstructive sleep apnea include weight loss for the obese patient, Nasal-continuous positive Airway Pressure (a facemask used at night which produces a positive pressure within the upper airway), pharyngeal surgery and the administration of a variety of pharmacologic agents which have not been proven to be entirely successful. Chest 109 (5):1346-1358 (May 1996) entitled Treatment of Obstructive Sleep Apnea, a Review, hereby incorporated by reference. These agents include Acetazolamide, Medroxyprogesterone, Opioid Antagonists, Nicotine, Angiotensin-Converting Enzyme Inhibitors and Psychotropic Agents (including those that prevent the reuptake of biogenic amines such as norepinephrine, dopamine and serotonin). Id. At 1353. Many of these pharmacological agents used also have a ventilatory depressant action (such as benzodiazepines) or other side effects such as urinary hesitancy and/or impotence in men (Protriptyline) so that a new agent with fewer side effects is needed for the treatment of obstructive sleep apnea. Even though serotonin is a sleep-inducing agent and may be a ventilatory stimulant (Id. At 1354), 5HT2A receptor antagonists have been found useful in treating obstructive sleep apnea. See also Am. J. Respir Crit Care Med (153) pp 776-786 (1996) where serotonin antagonists exacerbated sleep apnea produced in English bulldogs. But compare, Journal of Physiology (466) pp 367-382 (1993), where it is postulated that an excess of serotonin due to dysfunction of the serotonin biosynthesis mechanisms might set up conditions which favor obstructive apneas; European Journal of Pharmacology (259):71-74 (1994) further work on rat model with 5HT2 antagonist.
EP 1 262 197 discloses a method of treating sleep disorders including sleep apnea by administering to a patient in need of such a treatment a 5HT1A antagonist or an alpha-2-adrenergic antagonist in combination with an antidepressant such as serotonin reuptake inhibitor (SRI). Such a combination exhibits an improvement in efficacy.
U.S. Pat. No. 6,143,792 discloses that a specific 5HT2A receptor antagonist is useful in the treatment of the sleep apnea syndrome. Similarly, U.S. Pat. No. 6,576,670 discloses that a specific 5HT2A and 5HT2A/C receptor antagonist is useful in the treatment of snoring and upper airway high resistance syndrome.
U.S. Pat. No. 6,277,864 discloses that a specific 5HT2A receptor antagonist is useful in the treatment of a variety of sleep disorders.
All of the references described herein are incorporated herein by reference in their entirety.
However, there is still a need for developing a compound that not only exhibits selective 5HT2A antagonistic activity but also exhibits improved safety properties with no or minimal side-effects.
Accordingly, it is an object of this invention to provide a series of dialkylamino, piperidinyl or piperazinyl substituted bis aryl and heteroaryl derivatives which are potent, selective serotonin, 5HT2A, antagonists.
It is also an object of this invention to provide processes for the preparation of the dialkylamino, piperidinyl or piperazinyl substituted bis aryl and heteroaryl derivatives as disclosed herein.
Other objects and further scope of the applicability of the present invention will become apparent from the detailed description that follows.